Project 3 - QUANTITATIVE METHODS RESEARCH PROJECT - Abstract Over the past three decades, there have been great advances in HIV research, especially in diagnostics and treatment. Curing HIV will require further advances, particularly in the development of new agents and methods for evaluating incremental improvements in their contribution to cure. Our proposed Revealing Reservoirs during Rebound (R3) program will use a large battery of new technologies to investigate how HIV persists in and populates reservoirs throughout the body. Such new insights will be crucial in developing strategies aimed at curing HIV. To make maximal use of existing and newly generated data requires parallel advances in quantitative methods; hence, we propose a Quantitative Methods Research Project (RP). This RP will maximize the utility of data and samples collected in the overall program through the development of novel approaches for their analysis. The aims of our Quantitative Methods RP include: Aim 1: Discover biomarkers that can predict viral rebound when antiretroviral therapy (ART) is stopped to help guide future curative strategies. Aim 2: Precisely characterize HIV populations in T cell subsets and throughout the body and the impact of treatment interruption and re-initiation on these viral populations. Aim 3: Determine immune mechanisms by which HIV populations persist during ART by measuring biological quantities associated with viral rebound dynamics after stopping ART, and HIV population dynamics in cellular subsets and anatomic compartments. Aim 4: Create a global host model that uses mechanistic and empiric modeling methods to integrate our observations from viral rebound dynamics, HIV population of T cell subsets and tissues, and immunologic and virologic quantities to better understand the HIV in the body and the factors that sustain HIV persistence during ART and contribute to viral rebound when ART is stopped. The successful completion of these aims will provide the analytical framework to better understand the mechanistic underpinning of how HIV persists in the setting of ART, and what factors may be attractive targets to disrupt this viral persistence.